Among nuclear receptors, PPAR (Peroxisome Proliferator Activated Receptor) is known to have three subtypes, which are PPARα, PPARγ and PPARδ (Nature, 1990, 347, p 645-650, Proc. Natl. Acad. Sci. USA 1994, 91, p 7335-7359). PPARα, PPARγ and PPARδ have tissue specific functions in vivo and different regions for expression. PPARα is mainly expressed in the heart, kidney, skeletal muscle and large intestine in human (Mol. Pharmacol. 1998, 53, p 14-22, Toxicol. Lett. 1999, 110, p 119-127, J. Biol. Chem. 1998, 273, p 16710-16714), and is involved in β-oxidation of peroxisome and mitochondria (Biol. Cell. 1993, 77, p 67-76, J. Biol. Chem. 1997, 272, p 27307-27312). PPARγ is expressed in the skeletal muscle at a low level but mainly expressed in the adipose tissue to induce the adipocyte differentiation and to store energy as the form of fat, and is involved in homeostatic regulation of insulin and glucose (Moll. Cell. 1999, 4, p 585-594, p 597-609, p 611-617). PPARδ, is preserved evolutionarily in mammals including human and vertebrates including rodents and sea squirts. The first PPARδ found in Xenopus laevis was known as PPARβ (Cell 1992, 68, p 879-887) and PPARδ found in human was named differently as NUC1 (Mol. Endocrinol. 1992, 6, p 1634-1641), PPARδ (Proc. Natl. Acad. Sci. USA 1994, 91, p 7355-7359), NUC1 (Biochem. Biophys. Res. Commun. 1993, 196, p 671-677), FAAR (J. Bio. Chem. 1995, 270, p 2367-2371), ect, but they have been renamed as PPARδ recently. In human, PPARδ is known to exist in chromosome 6p21.1-p21.2. In rats, PPARδ mRNA is found in various cells but the level is lower than those of PPARα or PPARγ (Endocrinology 1996, 137, p 354-366, J. Bio. Chem. 1995, 270, p 2367-2371, Endocrinology 1996, 137, p 354-366). The previous studies confirmed that PPARδ plays an important role in the reproductive cell expression (Genes Dev. 1999, 13, p 1561-1574) and has physiological functions of differentiating neuronal cells (J. Chem. Neuroanat 2000, 19, p 225-232) in central nervous system (CNS) and wound healing with anti-inflammatory effect (Genes Dev. 2001, 15, p 3263-3277, Proc. Natl. Acad. Sci. USA 2003, 100, p 6295-6296). Recent studies also confirmed that PPARδ is involved in the adipocyte differentiation and lipid metabolism (Proc. Natl. Acad. Sci. USA 2002, 99, p 303-308, Mol. Cell. Biol. 2000, 20, p 5119-5128). For example, PPARδ activates the expression of key gene involved in β-oxidation in fatty acid catabolism and uncoupling proteins (UCPs), the gene involved in energy metabolism, which brings the effect of improving obesity (Nature 2000, 406, p 415-418, Cell 2003, 113, p 159-170, PLoS Biology 2004, 2, p 1532-1539). The activation of PPARδ increases the HDL level, improves type 2 diabetes without weight changes (Proc. Natl. Acad. Sci. USA 2001, 98, p 5306-5311, 2003, 100, p 15924-15929, 2006, 103, p 3444-3449), and favors the treatment of arteriosclerosis by inhibiting the gene associated with arteriosclerosis (Science, 2003, 302, p 453-457). Therefore, studies on the regulation of lipid metabolism using PPARδ provide a clue to develop a treatment method for obesity, diabetes, hyperlipidemia and arteriosclerosis.
PPARδ is involved in the mitochondria generation and the muscle fiber conversion in muscles to enhance endurance. Muscles have fatty acid catabolism muscle fiber (Type I) that enhances endurance and glycoclastic muscle fiber (Type that enhances power. Fatty acid catabolism muscle fiber (Type I) which is responsible for enhancing endurance is red because it has plenty of mitochondria and myoglobin. In the meantime, glycoclastic muscle fiber (Type II) which is responsible for enhancing power is white. When PPARδ was artificially over-expressed in the rat muscles, Type I muscle fiber was increased significantly, in addition to the increase of myoglobin, electron transport system enzymes (cytochrome c, cytochrome c oxidases II and IV) and fatty acid β oxidase. Therefore, constant running time and distance were respectively 67% and 92% increased, compared with wild type rats (PLoS Biology, 2004, 2:e294).
Synthetic PPARδ ligands developed so far have less selectivity, compared with other PPARα and PPARγ ligands. The early selective ligand was L-631033, developed by Merk (J. Steroid Biochem. Mol. Biol. 1997, 63, p 1-8), which was produced by introducing a functional group being able to fix side chain based on its natural fatty acid morphology. The same research team reported later more effective ligand L-165041 (J. Med. Chem. 1996, 39, p 2629-2654), in which the compound known as a leukotriene agonist is functioning to activate human PPARδ. This compound exhibited great selectivity to hPPARδ, which is 10 times the selectivity to PPARα or PPARγ. And EC50 of the compound was 530 nM. Other ligands L-796449 and L-783483 have improved affinity (EC50=7.9 nM) but barely have selectivity to other hPPAR subtypes.
The PPARδ selective ligand GW501516 ([2-methyl-4-[[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methyl]sulfanyl]phenoxy]acetic acid), developed by GlaxoSmithKline, exhibits much better physiological effect than any other ligands previously developed (Proc. Natl. Acad. Sci. USA 2001, 98, p 5306-5311).

The GW501516 has excellent affinity (1-10 nM) to PPARδ, and excellent selectivity to PPARα or PPARγ as well, which is at least 1000 times the selectivity of earlier ligands.
The thiazole compound represented by formula A as a PPARδ selective activator has been described in WO 2001-00603 and WO 2002-62774 applied by Glaxo group and WO 2003-072100 applied by Eli Lilly.

[Wherein, R′ is CF3 or F, R″ is H, CH3 or Cl, R′″ is H, CH3 or CH2CH3, and R″″ is H, alkyl or aryl alkyl.]
However, the PPARδ activity induced by all the ligands developed so far is only resulted from 30-40% of total ligand-binding pockets.